Researchers Discover Uncharted Territory in Pre-Clinical Alzheimer's

The earliest maps of a new land, when viewed beside contemporary maps, often have the look of a child's drawing. The borders are rough, whole regions are missing, others misrepresented. If people followed such a map, they might get terribly lost. And yet, some map is better than none at all.

This week, at the Alzheimer's Association International Conference in Vancouver, researchers from the Mayo Clinic reported results of their study of potential biomarkers for preclinical Alzheimer's disease. "Biomarker," a relatively new term in medicine, is a kind of shorthand for any of the various hints that clue us in to the complex ways in which a disease develops. In Alzheimer's disease research, the most studied biomarkers include MRI and PET scan images of the brain.

Their results suggest that among cognitively normal older adults there is a potentially large population who occupy an uncharted territory. Their biomarker results are neither normal, nor clearly abnormal. Dr. David Knopman, the investigator who presented the results, admitted that he and his colleagues "hadn't expected to encounter this result."

One of the biomarkers in question comes in the form of MRI images that show parts of the brain that are atrophied -- areas in which the death of brain cells has "shrunk" the brain. The other set of biomarkers involves two kinds of PET images -- one that measures brain metabolism and the other measures amyloid plaques, which are dense deposits of protein believed to be the "signature" of Alzheimer's disease.

Researchers have embraced these biomarkers because, although they have not discovered what causes this complex disease that develops over a lifetime, they are convinced that discovering its biomarkers is the key to transforming the diagnosis. They hope these advances mean we may one day go from relying on a physician's history and physical exam to determine whether a patient has dementia to a continuum that a physician can diagnose even before a person is ill simply by measuring the presence of so-called "biomarker signatures."

The Mayo Clinic researchers focused on the proposed biomarkers of preclinical Alzheimer's disease, a developing concept that describes individuals who are outwardly normal, but who have the amyloid plaques seen in Alzheimer's disease. Researchers are guessing that, if followed over time, these people will progress to mild cognitive impairment -- notable memory loss with retained ability to engage in day-to-day tasks -- and, ultimately, dementia. Their goal was to use the MRI and PET biomarker results to classify their subjects into the proposed stages of preclinical Alzheimer's disease, follow them for at least a year, and then restage them.

Preclinical Alzheimer's disease is truly at the uncharted frontier between what is a normal versus a diseased brain, a frontier that entices us to explore it. Discovering its biomarkers promises to reveal an early diagnosis and interventions to prevent cognitive impairment. But exploring it is not without peril. If we discover that biomarkers behave in ways that do not fit with what we expected, then we risk labeling otherwise healthy older adults with something we do not understand.